Synapse weakening in the pathophysiology of Alzheimer’s disease

Lead Research Organisation: King's College London

Abstract

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Technical Summary

The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019.

The pathophysiology of Alzheimer’s disease (AD) involves the weakening of synaptic connections and ultimately their elimination, which is thought to correlate with disease progression and severity. This positions synapse weakening as an early and pivotal point in AD pathogenesis and an important therapeutic target. Changes to the synaptic expression of AMPA receptors (AMPAR) are considered a major component of synaptic plasticity and connectivity, which are severely dysregulated by disease. Evidence suggests that synaptic dysfunction and aberrant decomposition of dendritic spines occurs prior to Aß/Tau plaque and tangle formation. The focus of this programme is to explore the role of AMPAR endocytosis in synaptic dysfunction and its contribution to neurodegeneration. We have previously shown that the caspase-3 ? Akt1 ? glycogen synthase kinase-3 beta (GSK-3ß) ? phosphorylation of tau (pTau) cascade is involved in Aß-mediated pathophysiological synaptic dysfunction in the hippocampus. Therefore, we hypothesise that synapse loss in disease is underpinned by the aberrant activation of synapse weakening signalling cascades. During this programme, we seek to address three specific questions: 1) Which factors modulate the cellular and molecular mechanisms of ‘synapse weakening’ by AD-associated pathophysiology? 2) What are the effects of neuronal activity on the pathophysiology of synapse weakening, and what are the impacts on synapse health? 3) Which synapse weakening molecules and markers are prevalent in AD brain tissue?

Publications

10 25 50
 
Description MRC (UK)-Korea Ministry of Science & Technology, Multi-omics research programme
Geographic Reach Africa 
Policy Influence Type Implementation circular/rapid advice/letter to e.g. Ministry of Health
 
Description MRC-KHIDI collaboration research programme
Geographic Reach Asia 
Policy Influence Type Implementation circular/rapid advice/letter to e.g. Ministry of Health
 
Description 11th UK-Korea Neuroscience Symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact MRC funded UK-Korea Neuroscience Symposium. 250 Neuroscientists attended and discuss about neurodegeneration and synaptic dysfunction.
Year(s) Of Engagement Activity 2018
 
Description Invited Seminar, Keio University, Tokyo Japan 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact 150 post/under graduate students and postdoctoral researchers and academics attended and discussed about new pathway of synapse weakening in Alzheimer's disease.
Year(s) Of Engagement Activity 2018
 
Description UK-DRI Connectome 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact UK-DRI annual symposium. Director, Associated-Directors and program leaders present their view and plan for DRI research projects.
Year(s) Of Engagement Activity 2018
 
Description UK-Japan Neuroscience Symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact MRC (UK) and AMED (Japan) funded Neuroscience Symposium. UK & Japan Neuroscientists presented and discussed about new scientific data.
Year(s) Of Engagement Activity 2019